Pandas Profiling Report

Dataset statistics

Number of variables	15
Number of observations	851
Missing cells	1810
Missing cells (%)	14.2%
Duplicate rows	0
Duplicate rows (%)	0.0%
Total size in memory	89.1 KiB
Average record size in memory	107.2 B

Variable types

Boolean	1
Text	9
Numeric	2
Categorical	1
Unsupported	2

Alerts

`pubmed_type` has constant value "article"	Constant
`pubmed_id` is highly overall correlated with `year`	High correlation
`year` is highly overall correlated with `pubmed_id`	High correlation
`include` is highly imbalanced (83.9%)	Imbalance
`abstract` has 21 (2.5%) missing values	Missing
`first_author` has 12 (1.4%) missing values	Missing
`doi` has 67 (7.9%) missing values	Missing
`webofscience_id` has 851 (100.0%) missing values	Missing
`central_id` has 851 (100.0%) missing values	Missing
`pubmed_id` has unique values	Unique
`webofscience_id` is an unsupported type, check if it needs cleaning or further analysis	Unsupported
`central_id` is an unsupported type, check if it needs cleaning or further analysis	Unsupported

Reproduction

Analysis started	2024-07-04 14:23:44.881938
Analysis finished	2024-07-04 14:23:46.622335
Duration	1.74 second
Software version	ydata-profiling v4.8.3
Download configuration	config.json

include
Boolean

IMBALANCE

Distinct	2
Distinct (%)	0.2%
Missing	0
Missing (%)	0.0%
Memory size	983.0 B

False	831
True	20

Common Values (Table)
Common Values (Plot)

Value	Count	Frequency (%)
False	831	97.6%
True	20	2.4%

title
Text

Distinct	850
Distinct (%)	99.9%
Missing	0
Missing (%)	0.0%
Memory size	6.8 KiB

Length

Max length	232
Median length	148
Mean length	99.376028
Min length	4

Characters and Unicode

Total characters	84569
Distinct characters	107
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	849 ?
Unique (%)	99.8%

Sample

1st row	The effectiveness of clonidine as an analgesic in paediatric adenotonsillectomy
2nd row	A Controlled Trial of Sustained-Release Bupropion, a Nicotine Patch, or Both for Smoking Cessation
3rd row	Effects of methylphenidate on complex cognitive processing in attention-deficit hyperactivity disorder.
4th row	Spinal Clonidine Prolongs Labor Analgesia from Spinal Sufentanil and Bupivacaine
5th row	Low-Dose Clozapine for the Treatment of Drug-Induced Psychosis in Parkinson's Disease

Value	Count	Frequency (%)
of	758	7.2%
in	491	4.7%
and	450	4.3%
the	302	2.9%
with	278	2.6%
a	239	2.3%
treatment	156	1.5%
for	147	1.4%
disorder	141	1.3%
patients	127	1.2%
Other values (2116)	7455	70.7%

Most occurring characters

Value	Count	Frequency (%)
	9700	11.5%
e	7703	9.1%
i	6996	8.3%
n	5960	7.0%
t	5534	6.5%
o	5417	6.4%
a	5382	6.4%
r	4120	4.9%
s	3562	4.2%
l	2930	3.5%
Other values (97)	27265	32.2%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	84569	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
	9700	11.5%
e	7703	9.1%
i	6996	8.3%
n	5960	7.0%
t	5534	6.5%
o	5417	6.4%
a	5382	6.4%
r	4120	4.9%
s	3562	4.2%
l	2930	3.5%
Other values (97)	27265	32.2%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	84569	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
	9700	11.5%
e	7703	9.1%
i	6996	8.3%
n	5960	7.0%
t	5534	6.5%
o	5417	6.4%
a	5382	6.4%
r	4120	4.9%
s	3562	4.2%
l	2930	3.5%
Other values (97)	27265	32.2%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	84569	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
	9700	11.5%
e	7703	9.1%
i	6996	8.3%
n	5960	7.0%
t	5534	6.5%
o	5417	6.4%
a	5382	6.4%
r	4120	4.9%
s	3562	4.2%
l	2930	3.5%
Other values (97)	27265	32.2%

abstract
Text

MISSING

Distinct	830
Distinct (%)	100.0%
Missing	21
Missing (%)	2.5%
Memory size	6.8 KiB

Length

Max length	31173
Median length	1688.5
Mean length	1689.4952
Min length	109

Characters and Unicode

Total characters	1402281
Distinct characters	144
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	830 ?
Unique (%)	100.0%

Sample

1st row	To compare the analgesic effects of preoperative oral clonidine with intraoperative intravenous fentanyl in children undergoing tonsillectomy or adenotonsillectomy.This randomized, controlled, double-blind study of 36 ASA I-II children, age 7-12 yr undergoing adenotonsillectomy was conducted at a tertiary care paediatric teaching hospital. Either 4 micrograms.kg-1 clonidine po was given 60-90 min preoperatively or 3 micrograms.kg-1 fentanyl i.v. was given intraoperatively. Postoperatively visual analog pain scores (VAS) were recorded at rest and on swallowing every 10 min for the first 30 min and then every 15 min for two hours. Morphine 0.05 mg.kg-1 i.v. was given for VAS > or = 5. If > 3 doses were required, 1.5 mg.kg-1 codeine po and 20 mg.kg-1 acetaminophen po were given. Sedation and anxiety scores were recorded preoperatively. Haemodynamic changes, blood loss, recovery scores, and the incidence of vomiting, hypotension, and airway obstruction were recorded.Children who received clonidine had a higher incidence of preoperative sedation (63%) than those receiving fentanyl (6%). Preinduction mean arterial pressure was lower in the clonidine group but required no intervention. VAS scores were similar throughout the observation period. There was no difference either in the number of morphine or codeine rescue doses administered or in the incidence of side effects.Oral clonidine is an effective analgesic and sedative for children undergoing tonsillectomy or adenotonsillectomy.
2nd row	Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8.
3rd row	Three experiments were conducted to explore the effects of methylphenidate (MPH), attention-deficit hyperactivity disorder (ADHD) diagnosis, and age on performance on a complex visual-memory search task. Results showed that the effects of MPH varied with information load. On low-processing loads, all doses of MPH helped children with ADHD to improve accuracy with no cost to reaction time (RT), whereas on high loads, higher MPH doses improved error rates while slowing RT. Without medication, children with ADHD showed high error rates and slow RTs across both low and high loads, as did younger, normal control children. Because MPH slowed performance on only the most difficult, high-load conditions, it is argued that the drug improves self-regulatory ability, enabling children with ADHD to adapt differentially to high and low loads.
4th row	We sought to determine whether spinal clonidine 50 [micro sign]g prolongs the analgesia from the spinal administration of sufentanil 7.5 [micro sign]g and bupivacaine 2.5 mg early in the first stage of labor. Thirty patients were randomized to receive a 2-mL spinal injection of sufentanil 7.5 [micro sign]g + bupivacaine 2.5 mg with or without clonidine 50 [micro sign]g using a combined spinal-epidural (CSE) technique. Pain, nausea, pruritus, sedation, motor block, blood pressure, and heart rate were assessed until the patient requested additional analgesia. Analgesia was significantly prolonged in patients who received spinal sufentanil + bupivacaine + clonidine (197 +/- 70 vs 132 +/- 39 min; P = 0.004). Pain scores and side effects, including motor block, sedation, and hypotension, were similar between groups. Spinal clonidine significantly prolongs labor analgesia from spinal sufentanil and bupivacaine without producing serious adverse side effects. Implications: We studied the effects of spinal clonidine administered with spinal sufentanil and bupivacaine on labor analgesia using a combined spinal-epidural technique and conclude that spinal clonidine significantly prolongs labor analgesia from spinal sufentanil and bupivacaine without producing serious adverse effects. (Anesth Analg 1999;88:573-76)
5th row	Drug-induced psychosis is a difficult problem to manage in patients with Parkinson's disease. Multiple open-label studies have reported that treatment with clozapine at low doses ameliorates psychosis without worsening parkinsonism.We conducted a randomized, double-blind, placebo-controlled trial of low doses of clozapine (6.25 to 50 mg per day) in 60 patients at six sites over a period of 14 months. The patients (mean age, 72 years) had idiopathic Parkinson's disease and drug-induced psychosis of at least four weeks' duration. All the patients continued to receive fixed doses of antiparkinsonian drugs during the four weeks of the trial. Blood counts were monitored weekly in all the patients.The mean dose of clozapine was 24.7 mg per day. The patients in the clozapine group had significantly more improvement than those in the placebo group in all three of the measures used to determine the severity of psychosis. The mean (+/-SE) scores on the Clinical Global Impression Scale improved by 1.6+/-0.3 points for the patients receiving clozapine, as compared with 0.5+/-0.2 point for those receiving placebo (P<0.001). The score on the Brief Psychiatric Rating Scale improved by 9.3+/-1.5 points for the patients receiving clozapine, as compared with 2.6+/-1.3 points for those receiving placebo (P=0.002). The score on the Scale for the Assessment of Positive Symptoms improved by 11.8+/-2.0 points for the patients receiving clozapine, as compared with 3.8+/-1.9 points for those receiving placebo (P=0.01). Seven patients treated with clozapine had an improvement of at least three on the seven-point Clinical Global Impression Scale, as compared with only one patient given placebo. Clozapine treatment improved tremor and had no deleterious effect on the severity of parkinsonism. In one patient, clozapine was discontinued because of leukopenia.Clozapine, at daily doses of 50 mg or less, is safe and significantly improves drug-induced psychosis without worsening parkinsonism.

Value	Count	Frequency (%)
the	8276	4.1%
of	8038	4.0%
and	6724	3.4%
in	5188	2.6%
to	3685	1.8%
with	3260	1.6%
a	2984	1.5%
were	2321	1.2%
for	2268	1.1%
patients	2042	1.0%
Other values (14757)	155521	77.6%

Most occurring characters

Value	Count	Frequency (%)
	199377	14.2%
e	136553	9.7%
i	94159	6.7%
t	91663	6.5%
a	89539	6.4%
n	84057	6.0%
o	81214	5.8%
r	70434	5.0%
s	68612	4.9%
d	48157	3.4%
Other values (134)	438516	31.3%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	1402281	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
	199377	14.2%
e	136553	9.7%
i	94159	6.7%
t	91663	6.5%
a	89539	6.4%
n	84057	6.0%
o	81214	5.8%
r	70434	5.0%
s	68612	4.9%
d	48157	3.4%
Other values (134)	438516	31.3%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	1402281	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
	199377	14.2%
e	136553	9.7%
i	94159	6.7%
t	91663	6.5%
a	89539	6.4%
n	84057	6.0%
o	81214	5.8%
r	70434	5.0%
s	68612	4.9%
d	48157	3.4%
Other values (134)	438516	31.3%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	1402281	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
	199377	14.2%
e	136553	9.7%
i	94159	6.7%
t	91663	6.5%
a	89539	6.4%
n	84057	6.0%
o	81214	5.8%
r	70434	5.0%
s	68612	4.9%
d	48157	3.4%
Other values (134)	438516	31.3%

first_author
Text

MISSING

Distinct	697
Distinct (%)	83.1%
Missing	12
Missing (%)	1.4%
Memory size	6.8 KiB

Length

Max length	31
Median length	20
Mean length	9.2574493
Min length	4

Characters and Unicode

Total characters	7767
Distinct characters	68
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	598 ?
Unique (%)	71.3%

Sample

1st row	Reimer EJ
2nd row	Jorenby DE
3rd row	Berman T
4th row	D'Angelo R
5th row	Parkinson Study Group

Value	Count	Frequency (%)
m	51	3.0%
j	33	1.9%
s	30	1.8%
r	25	1.5%
p	19	1.1%
a	18	1.1%
t	18	1.1%
k	15	0.9%
jm	15	0.9%
d	15	0.9%
Other values (911)	1457	85.9%

Most occurring characters

Value	Count	Frequency (%)
	857	11.0%
e	573	7.4%
a	511	6.6%
n	464	6.0%
r	401	5.2%
i	377	4.9%
o	361	4.6%
l	281	3.6%
s	241	3.1%
M	221	2.8%
Other values (58)	3480	44.8%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	7767	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
	857	11.0%
e	573	7.4%
a	511	6.6%
n	464	6.0%
r	401	5.2%
i	377	4.9%
o	361	4.6%
l	281	3.6%
s	241	3.1%
M	221	2.8%
Other values (58)	3480	44.8%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	7767	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
	857	11.0%
e	573	7.4%
a	511	6.6%
n	464	6.0%
r	401	5.2%
i	377	4.9%
o	361	4.6%
l	281	3.6%
s	241	3.1%
M	221	2.8%
Other values (58)	3480	44.8%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	7767	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
	857	11.0%
e	573	7.4%
a	511	6.6%
n	464	6.0%
r	401	5.2%
i	377	4.9%
o	361	4.6%
l	281	3.6%
s	241	3.1%
M	221	2.8%
Other values (58)	3480	44.8%

year
Real number (ℝ)

HIGH CORRELATION

Distinct	12
Distinct (%)	1.4%
Missing	0
Missing (%)	0.0%
Infinite	0
Infinite (%)	0.0%
Mean	1999.2186

Minimum	1982
Maximum	2003
Zeros	0
Zeros (%)	0.0%
Negative	0
Negative (%)	0.0%
Memory size	1.8 KiB

Quantile statistics

Minimum	1982
5-th percentile	1994
Q1	1997
median	2000
Q3	2002
95-th percentile	2003
Maximum	2003
Range	21
Interquartile range (IQR)	5

Descriptive statistics

Standard deviation	2.9074644
Coefficient of variation (CV)	0.0014543004
Kurtosis	0.32424354
Mean	1999.2186
Median Absolute Deviation (MAD)	2
Skewness	-0.61108752
Sum	1701335
Variance	8.453349
Monotonicity	Not monotonic

Histogram with fixed size bins (bins=12)

Value	Count	Frequency (%)
2002	141	16.6%
2001	107	12.6%
2003	107	12.6%
1999	85	10.0%
1998	84	9.9%
1997	83	9.8%
2000	78	9.2%
1994	59	6.9%
1996	51	6.0%
1995	44	5.2%
Other values (2)	12	1.4%

Minimum 10 values
Maximum 10 values

Value	Count	Frequency (%)
1982	1	0.1%
1993	11	1.3%
1994	59	6.9%
1995	44	5.2%
1996	51	6.0%
1997	83	9.8%
1998	84	9.9%
1999	85	10.0%
2000	78	9.2%
2001	107	12.6%

Value	Count	Frequency (%)
2003	107	12.6%
2002	141	16.6%
2001	107	12.6%
2000	78	9.2%
1999	85	10.0%
1998	84	9.9%
1997	83	9.8%
1996	51	6.0%
1995	44	5.2%
1994	59	6.9%

journal
Text

Distinct	233
Distinct (%)	27.4%
Missing	0
Missing (%)	0.0%
Memory size	6.8 KiB

Length

Max length	46
Median length	32
Mean length	16.556992
Min length	3

Characters and Unicode

Total characters	14090
Distinct characters	51
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	131 ?
Unique (%)	15.4%

Sample

1st row	Can J Anaesth
2nd row	N Engl J Med
3rd row	J Abnorm Psychol
4th row	Anesth Analg
5th row	N Engl J Med

Value	Count	Frequency (%)
j	357	16.2%
psychiatry	212	9.6%
clin	189	8.6%
psychopharmacol	81	3.7%
am	75	3.4%
anesth	56	2.5%
analg	43	1.9%
arch	41	1.9%
med	39	1.8%
res	37	1.7%
Other values (237)	1076	48.8%

Most occurring characters

Value	Count	Frequency (%)
	1355	9.6%
h	944	6.7%
a	939	6.7%
r	911	6.5%
c	779	5.5%
o	763	5.4%
i	746	5.3%
s	746	5.3%
l	728	5.2%
y	713	5.1%
Other values (41)	5466	38.8%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	14090	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
	1355	9.6%
h	944	6.7%
a	939	6.7%
r	911	6.5%
c	779	5.5%
o	763	5.4%
i	746	5.3%
s	746	5.3%
l	728	5.2%
y	713	5.1%
Other values (41)	5466	38.8%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	14090	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
	1355	9.6%
h	944	6.7%
a	939	6.7%
r	911	6.5%
c	779	5.5%
o	763	5.4%
i	746	5.3%
s	746	5.3%
l	728	5.2%
y	713	5.1%
Other values (41)	5466	38.8%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	14090	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
	1355	9.6%
h	944	6.7%
a	939	6.7%
r	911	6.5%
c	779	5.5%
o	763	5.4%
i	746	5.3%
s	746	5.3%
l	728	5.2%
y	713	5.1%
Other values (41)	5466	38.8%

doi
Text

MISSING

Distinct	784
Distinct (%)	100.0%
Missing	67
Missing (%)	7.9%
Memory size	6.8 KiB

Length

Max length	76
Median length	56
Mean length	43.035714
Min length	22

Characters and Unicode

Total characters	33740
Distinct characters	46
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	784 ?
Unique (%)	100.0%

Sample

1st row	https://doi.org/10.1007/bf03012457
2nd row	https://doi.org/10.1056/nejm199903043400903
3rd row	https://doi.org/10.1037/0021-843x.108.1.90
4th row	https://doi.org/10.1097/00000539-199903000-00020
5th row	https://doi.org/10.1056/nejm199903113401003

Value	Count	Frequency (%)
https://doi.org/10.3109/10401239409148989	1	0.1%
https://doi.org/10.1097/00000542-199905000-00020	1	0.1%
https://doi.org/10.1542/peds.103.4.730	1	0.1%
https://doi.org/10.1037/0021-843x.108.1.90	1	0.1%
https://doi.org/10.1097/00000539-199903000-00020	1	0.1%
https://doi.org/10.1056/nejm199903113401003	1	0.1%
https://doi.org/10.1001/archpsyc.56.3.241	1	0.1%
https://doi.org/10.4088/jcp.v60n0207	1	0.1%
https://doi.org/10.1016/s0893-133x(98)00093-1	1	0.1%
https://doi.org/10.1001/archinte.159.6.551	1	0.1%
Other values (774)	774	98.7%

Most occurring characters

Value	Count	Frequency (%)
0	5488	16.3%
1	3311	9.8%
/	3145	9.3%
.	2380	7.1%
o	1594	4.7%
t	1587	4.7%
9	1196	3.5%
2	1139	3.4%
s	1036	3.1%
p	1028	3.0%
Other values (36)	11836	35.1%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	33740	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
0	5488	16.3%
1	3311	9.8%
/	3145	9.3%
.	2380	7.1%
o	1594	4.7%
t	1587	4.7%
9	1196	3.5%
2	1139	3.4%
s	1036	3.1%
p	1028	3.0%
Other values (36)	11836	35.1%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	33740	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
0	5488	16.3%
1	3311	9.8%
/	3145	9.3%
.	2380	7.1%
o	1594	4.7%
t	1587	4.7%
9	1196	3.5%
2	1139	3.4%
s	1036	3.1%
p	1028	3.0%
Other values (36)	11836	35.1%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	33740	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
0	5488	16.3%
1	3311	9.8%
/	3145	9.3%
.	2380	7.1%
o	1594	4.7%
t	1587	4.7%
9	1196	3.5%
2	1139	3.4%
s	1036	3.1%
p	1028	3.0%
Other values (36)	11836	35.1%

pubmed_id
Real number (ℝ)

HIGH CORRELATION UNIQUE

Distinct	851
Distinct (%)	100.0%
Missing	0
Missing (%)	0.0%
Infinite	0
Infinite (%)	0.0%
Mean	10582124

Minimum	7478682
Maximum	14645311
Zeros	0
Zeros (%)	0.0%
Negative	0
Negative (%)	0.0%
Memory size	6.8 KiB

Quantile statistics

Minimum	7478682
5-th percentile	7803346.5
Q1	9299842.5
median	10671903
Q3	11972820
95-th percentile	12766205
Maximum	14645311
Range	7166629
Interquartile range (IQR)	2672977

Descriptive statistics

Standard deviation	1601327.6
Coefficient of variation (CV)	0.15132384
Kurtosis	-0.95323677
Mean	10582124
Median Absolute Deviation (MAD)	1334990
Skewness	-0.17500315
Sum	9.0053873 × 10⁹
Variance	2.5642499 × 10¹²
Monotonicity	Not monotonic

Histogram with fixed size bins (bins=50)

Value	Count	Frequency (%)
10051933	1	0.1%
7822629	1	0.1%
7831459	1	0.1%
7849498	1	0.1%
7869468	1	0.1%
7875111	1	0.1%
7887841	1	0.1%
7906539	1	0.1%
7909410	1	0.1%
7929019	1	0.1%
Other values (841)	841	98.8%

Minimum 10 values
Maximum 10 values

Value	Count	Frequency (%)
7478682	1	0.1%
7486097	1	0.1%
7491385	1	0.1%
7491391	1	0.1%
7509495	1	0.1%
7514366	1	0.1%
7525394	1	0.1%
7525541	1	0.1%
7527327	1	0.1%
7527565	1	0.1%

Value	Count	Frequency (%)
14645311	1	0.1%
14592280	1	0.1%
14581254	1	0.1%
14567163	1	0.1%
14562491	1	0.1%
14529800	1	0.1%
12944341	1	0.1%
12934987	1	0.1%
12933373	1	0.1%
12927004	1	0.1%

authors
Text

Distinct	828
Distinct (%)	97.3%
Missing	0
Missing (%)	0.0%
Memory size	6.8 KiB

Length

Max length	362
Median length	108
Mean length	54.601645
Min length	0

Characters and Unicode

Total characters	46466
Distinct characters	74
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	815 ?
Unique (%)	95.8%

Sample

1st row	Reimer EJ; Dunn GS; Montgomery CJ; Sanderson PM; Scheepers LD; Merrick PM
2nd row	Jorenby DE; Leischow SJ; Nides MA; Rennard SI; Johnston JA; Hughes AR; Smith SS; Muramoto ML; Daughton DM; Doan K; Fiore MC; Baker TB
3rd row	Berman T; Douglas VI; Barr RG
4th row	D'Angelo R; Evans E; Dean LA; Gaver R; Eisenach JC
5th row	Parkinson Study Group

Value	Count	Frequency (%)
m	239	2.8%
j	238	2.8%
a	198	2.3%
r	162	1.9%
s	161	1.9%
d	131	1.5%
c	105	1.2%
h	104	1.2%
p	102	1.2%
g	97	1.1%
Other values (3130)	7111	82.2%

Most occurring characters

Value	Count	Frequency (%)
	7809	16.8%
;	3413	7.3%
e	3034	6.5%
a	2676	5.8%
n	2310	5.0%
r	2213	4.8%
i	1837	4.0%
o	1792	3.9%
l	1452	3.1%
s	1277	2.7%
Other values (64)	18653	40.1%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	46466	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
	7809	16.8%
;	3413	7.3%
e	3034	6.5%
a	2676	5.8%
n	2310	5.0%
r	2213	4.8%
i	1837	4.0%
o	1792	3.9%
l	1452	3.1%
s	1277	2.7%
Other values (64)	18653	40.1%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	46466	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
	7809	16.8%
;	3413	7.3%
e	3034	6.5%
a	2676	5.8%
n	2310	5.0%
r	2213	4.8%
i	1837	4.0%
o	1792	3.9%
l	1452	3.1%
s	1277	2.7%
Other values (64)	18653	40.1%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	46466	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
	7809	16.8%
;	3413	7.3%
e	3034	6.5%
a	2676	5.8%
n	2310	5.0%
r	2213	4.8%
i	1837	4.0%
o	1792	3.9%
l	1452	3.1%
s	1277	2.7%
Other values (64)	18653	40.1%

pubmed_type
Categorical

CONSTANT

Distinct	1
Distinct (%)	0.1%
Missing	0
Missing (%)	0.0%
Memory size	6.8 KiB

article	851

Length

Max length	7
Median length	7
Mean length	7
Min length	7

Characters and Unicode

Total characters	5957
Distinct characters	7
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	0 ?
Unique (%)	0.0%

Sample

1st row	article
2nd row	article
3rd row	article
4th row	article
5th row	article

Common Values

Value	Count	Frequency (%)
article	851	100.0%

Length

Histogram of lengths of the category

Common Values (Plot)

Value	Count	Frequency (%)
article	851	100.0%

Most occurring characters

Value	Count	Frequency (%)
a	851	14.3%
r	851	14.3%
t	851	14.3%
i	851	14.3%
c	851	14.3%
l	851	14.3%
e	851	14.3%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	5957	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
a	851	14.3%
r	851	14.3%
t	851	14.3%
i	851	14.3%
c	851	14.3%
l	851	14.3%
e	851	14.3%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	5957	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
a	851	14.3%
r	851	14.3%
t	851	14.3%
i	851	14.3%
c	851	14.3%
l	851	14.3%
e	851	14.3%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	5957	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
a	851	14.3%
r	851	14.3%
t	851	14.3%
i	851	14.3%
c	851	14.3%
l	851	14.3%
e	851	14.3%

publication_types
Text

Distinct	138
Distinct (%)	16.2%
Missing	0
Missing (%)	0.0%
Memory size	6.8 KiB

Length

Max length	256
Median length	213
Mean length	116.43008
Min length	13

Characters and Unicode

Total characters	99082
Distinct characters	56
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	65 ?
Unique (%)	7.6%

Sample

1st row	D016430: Clinical Trial; D003160: Comparative Study; D016428: Journal Article; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't
2nd row	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't
3rd row	D016430: Clinical Trial; D018848: Controlled Clinical Trial; D016428: Journal Article; D013485: Research Support, Non-U.S. Gov't
4th row	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial
5th row	D016430: Clinical Trial; D016428: Journal Article; D016448: Multicenter Study; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't; D013487: Research Support, U.S. Gov't, P.H.S.

Value	Count	Frequency (%)
trial	1231	10.7%
article	825	7.2%
d016428	824	7.2%
journal	824	7.2%
clinical	712	6.2%
d016430	624	5.4%
controlled	598	5.2%
support	532	4.6%
gov't	532	4.6%
research	532	4.6%
Other values (61)	4236	36.9%

Most occurring characters

Value	Count	Frequency (%)
	10619	10.7%
l	5688	5.7%
r	5049	5.1%
i	4639	4.7%
0	4633	4.7%
a	4595	4.6%
o	4357	4.4%
e	3976	4.0%
t	3685	3.7%
4	3678	3.7%
Other values (46)	48163	48.6%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	99082	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
	10619	10.7%
l	5688	5.7%
r	5049	5.1%
i	4639	4.7%
0	4633	4.7%
a	4595	4.6%
o	4357	4.4%
e	3976	4.0%
t	3685	3.7%
4	3678	3.7%
Other values (46)	48163	48.6%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	99082	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
	10619	10.7%
l	5688	5.7%
r	5049	5.1%
i	4639	4.7%
0	4633	4.7%
a	4595	4.6%
o	4357	4.4%
e	3976	4.0%
t	3685	3.7%
4	3678	3.7%
Other values (46)	48163	48.6%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	99082	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
	10619	10.7%
l	5688	5.7%
r	5049	5.1%
i	4639	4.7%
0	4633	4.7%
a	4595	4.6%
o	4357	4.4%
e	3976	4.0%
t	3685	3.7%
4	3678	3.7%
Other values (46)	48163	48.6%

mesh
Text

Distinct	849
Distinct (%)	99.8%
Missing	0
Missing (%)	0.0%
Memory size	6.8 KiB

Length

Max length	825
Median length	473
Mean length	375.84489
Min length	74

Characters and Unicode

Total characters	319844
Distinct characters	71
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	847 ?
Unique (%)	99.5%

Sample

1st row	D000082: Acetaminophen; D000233: Adenoidectomy; D000284: Administration, Oral; D000700: Analgesics; D018712: Analgesics, Non-Narcotic; D000701: Analgesics, Opioid; D001794: Blood Pressure; D002648: Child; D003000: Clonidine; D003061: Codeine; D003243: Consciousness; D003679: Deglutition; D004311: Double-Blind Method; D005260: Female; D005283: Fentanyl; D005500: Follow-Up Studies; D006801: Humans; D015994: Incidence; D007275: Injections, Intravenous; D007430: Intraoperative Care; D008297: Male; D009020: Morphine; D010147: Pain Measurement; D010149: Pain, Postoperative; D011292: Premedication; D014068: Tonsillectomy
2nd row	D000279: Administration, Cutaneous; D000328: Adult; D018687: Antidepressive Agents, Second-Generation; D016642: Bupropion; D003692: Delayed-Action Preparations; D004359: Drug Therapy, Combination; D005260: Female; D006801: Humans; D008297: Male; D009538: Nicotine; D016540: Smoking Cessation; D013375: Substance Withdrawal Syndrome; D015430: Weight Gain
3rd row	D000293: Adolescent; D000367: Age Factors; D001289: Attention Deficit Disorder with Hyperactivity; D000697: Central Nervous System Stimulants; D002648: Child; D003071: Cognition; D004305: Dose-Response Relationship, Drug; D005260: Female; D006801: Humans; D008297: Male; D008568: Memory; D008774: Methylphenidate; D011597: Psychomotor Performance; D011930: Reaction Time; D014796: Visual Perception
4th row	D000328: Adult; D016362: Analgesia, Obstetrical; D000700: Analgesics; D000701: Analgesics, Opioid; D000779: Anesthetics, Local; D002045: Bupivacaine; D003000: Clonidine; D004357: Drug Synergism; D004359: Drug Therapy, Combination; D005260: Female; D006801: Humans; D007278: Injections, Spinal; D017409: Sufentanil
5th row	D000368: Aged; D000978: Antiparkinson Agents; D014150: Antipsychotic Agents; D003024: Clozapine; D004311: Double-Blind Method; D005260: Female; D006801: Humans; D008297: Male; D010300: Parkinson Disease; D011605: Psychoses, Substance-Induced; D016896: Treatment Outcome

Value	Count	Frequency (%)
d006801	848	2.5%
humans	848	2.5%
male	643	1.9%
d008297	641	1.9%
d005260	586	1.7%
female	586	1.7%
aged	555	1.6%
adult	481	1.4%
d000328	481	1.4%
method	439	1.3%
Other values (2970)	27891	82.0%

Most occurring characters

Value	Count	Frequency (%)
	33148	10.4%
0	28251	8.8%
e	19303	6.0%
i	14915	4.7%
D	14792	4.6%
:	12461	3.9%
t	12055	3.8%
n	11987	3.7%
;	11610	3.6%
a	11520	3.6%
Other values (61)	149802	46.8%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	319844	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
	33148	10.4%
0	28251	8.8%
e	19303	6.0%
i	14915	4.7%
D	14792	4.6%
:	12461	3.9%
t	12055	3.8%
n	11987	3.7%
;	11610	3.6%
a	11520	3.6%
Other values (61)	149802	46.8%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	319844	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
	33148	10.4%
0	28251	8.8%
e	19303	6.0%
i	14915	4.7%
D	14792	4.6%
:	12461	3.9%
t	12055	3.8%
n	11987	3.7%
;	11610	3.6%
a	11520	3.6%
Other values (61)	149802	46.8%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	319844	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
	33148	10.4%
0	28251	8.8%
e	19303	6.0%
i	14915	4.7%
D	14792	4.6%
:	12461	3.9%
t	12055	3.8%
n	11987	3.7%
;	11610	3.6%
a	11520	3.6%
Other values (61)	149802	46.8%

webofscience_id
Unsupported

MISSING REJECTED UNSUPPORTED

Missing	851
Missing (%)	100.0%
Memory size	6.8 KiB

central_id
Unsupported

MISSING REJECTED UNSUPPORTED

Missing	851
Missing (%)	100.0%
Memory size	6.8 KiB

openalex_id
Text

Distinct	843
Distinct (%)	100.0%
Missing	8
Missing (%)	0.9%
Memory size	6.8 KiB

Length

Max length	32
Median length	32
Mean length	31.924081
Min length	30

Characters and Unicode

Total characters	26912
Distinct characters	26
Distinct categories	1 ?
Distinct scripts	1 ?
Distinct blocks	1 ?

The Unicode Standard assigns character properties to each code point, which can be used to analyse textual variables.

Unique

Unique	843 ?
Unique (%)	100.0%

Sample

1st row	https://openalex.org/W2082613933
2nd row	https://openalex.org/W2312609348
3rd row	https://openalex.org/W2022904832
4th row	https://openalex.org/W2021097359
5th row	https://openalex.org/W4239283954

Value	Count	Frequency (%)
https://openalex.org/w2082613933	1	0.1%
https://openalex.org/w135184902	1	0.1%
https://openalex.org/w2108061862	1	0.1%
https://openalex.org/w1987365003	1	0.1%
https://openalex.org/w2022904832	1	0.1%
https://openalex.org/w2021097359	1	0.1%
https://openalex.org/w4239283954	1	0.1%
https://openalex.org/w2154849243	1	0.1%
https://openalex.org/w1993818042	1	0.1%
https://openalex.org/w1561544516	1	0.1%
Other values (833)	833	98.8%

Most occurring characters

Value	Count	Frequency (%)
/	2529	9.4%
p	1686	6.3%
o	1686	6.3%
e	1686	6.3%
t	1686	6.3%
2	1218	4.5%
1	1076	4.0%
0	1048	3.9%
h	843	3.1%
.	843	3.1%
Other values (16)	12611	46.9%

Most occurring categories

Value	Count	Frequency (%)
(unknown)	26912	100.0%

Most frequent character per category

(unknown)

Value	Count	Frequency (%)
/	2529	9.4%
p	1686	6.3%
o	1686	6.3%
e	1686	6.3%
t	1686	6.3%
2	1218	4.5%
1	1076	4.0%
0	1048	3.9%
h	843	3.1%
.	843	3.1%
Other values (16)	12611	46.9%

Most occurring scripts

Value	Count	Frequency (%)
(unknown)	26912	100.0%

Most frequent character per script

(unknown)

Value	Count	Frequency (%)
/	2529	9.4%
p	1686	6.3%
o	1686	6.3%
e	1686	6.3%
t	1686	6.3%
2	1218	4.5%
1	1076	4.0%
0	1048	3.9%
h	843	3.1%
.	843	3.1%
Other values (16)	12611	46.9%

Most occurring blocks

Value	Count	Frequency (%)
(unknown)	26912	100.0%

Most frequent character per block

(unknown)

Value	Count	Frequency (%)
/	2529	9.4%
p	1686	6.3%
o	1686	6.3%
e	1686	6.3%
t	1686	6.3%
2	1218	4.5%
1	1076	4.0%
0	1048	3.9%
h	843	3.1%
.	843	3.1%
Other values (16)	12611	46.9%

year
pubmed_id

pubmed_id
year

pubmed_id
year

Auto

Heatmap
Table

	include	pubmed_id	year
include	1.000	0.077	0.083
pubmed_id	0.077	1.000	0.984
year	0.083	0.984	1.000

A simple visualization of nullity by column.

Nullity matrix is a data-dense display which lets you quickly visually pick out patterns in data completion.

The correlation heatmap measures nullity correlation: how strongly the presence or absence of one variable affects the presence of another.

First rows
Last rows

	include	title	abstract	first_author	year	journal	doi	pubmed_id	authors	pubmed_type	publication_types	mesh	webofscience_id	central_id	openalex_id
0	False	The effectiveness of clonidine as an analgesic in paediatric adenotonsillectomy	To compare the analgesic effects of preoperative oral clonidine with intraoperative intravenous fentanyl in children undergoing tonsillectomy or adenotonsillectomy.This randomized, controlled, double-blind study of 36 ASA I-II children, age 7-12 yr undergoing adenotonsillectomy was conducted at a tertiary care paediatric teaching hospital. Either 4 micrograms.kg-1 clonidine po was given 60-90 min preoperatively or 3 micrograms.kg-1 fentanyl i.v. was given intraoperatively. Postoperatively visual analog pain scores (VAS) were recorded at rest and on swallowing every 10 min for the first 30 min and then every 15 min for two hours. Morphine 0.05 mg.kg-1 i.v. was given for VAS > or = 5. If > 3 doses were required, 1.5 mg.kg-1 codeine po and 20 mg.kg-1 acetaminophen po were given. Sedation and anxiety scores were recorded preoperatively. Haemodynamic changes, blood loss, recovery scores, and the incidence of vomiting, hypotension, and airway obstruction were recorded.Children who received clonidine had a higher incidence of preoperative sedation (63%) than those receiving fentanyl (6%). Preinduction mean arterial pressure was lower in the clonidine group but required no intervention. VAS scores were similar throughout the observation period. There was no difference either in the number of morphine or codeine rescue doses administered or in the incidence of side effects.Oral clonidine is an effective analgesic and sedative for children undergoing tonsillectomy or adenotonsillectomy.	Reimer EJ	1998	Can J Anaesth	https://doi.org/10.1007/bf03012457	10051933	Reimer EJ; Dunn GS; Montgomery CJ; Sanderson PM; Scheepers LD; Merrick PM	article	D016430: Clinical Trial; D003160: Comparative Study; D016428: Journal Article; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't	D000082: Acetaminophen; D000233: Adenoidectomy; D000284: Administration, Oral; D000700: Analgesics; D018712: Analgesics, Non-Narcotic; D000701: Analgesics, Opioid; D001794: Blood Pressure; D002648: Child; D003000: Clonidine; D003061: Codeine; D003243: Consciousness; D003679: Deglutition; D004311: Double-Blind Method; D005260: Female; D005283: Fentanyl; D005500: Follow-Up Studies; D006801: Humans; D015994: Incidence; D007275: Injections, Intravenous; D007430: Intraoperative Care; D008297: Male; D009020: Morphine; D010147: Pain Measurement; D010149: Pain, Postoperative; D011292: Premedication; D014068: Tonsillectomy	None	None	https://openalex.org/W2082613933
1	False	A Controlled Trial of Sustained-Release Bupropion, a Nicotine Patch, or Both for Smoking Cessation	Use of nicotine-replacement therapies and the antidepressant bupropion helps people stop smoking. We conducted a double-blind, placebo-controlled comparison of sustained-release bupropion (244 subjects), a nicotine patch (244 subjects), bupropion and a nicotine patch (245 subjects), and placebo (160 subjects) for smoking cessation. Smokers with clinical depression were excluded. Treatment consisted of nine weeks of bupropion (150 mg a day for the first three days, and then 150 mg twice daily) or placebo, as well as eight weeks of nicotine-patch therapy (21 mg per day during weeks 2 through 7, 14 mg per day during week 8, and 7 mg per day during week 9) or placebo. The target day for quitting smoking was usually day 8.	Jorenby DE	1999	N Engl J Med	https://doi.org/10.1056/nejm199903043400903	10053177	Jorenby DE; Leischow SJ; Nides MA; Rennard SI; Johnston JA; Hughes AR; Smith SS; Muramoto ML; Daughton DM; Doan K; Fiore MC; Baker TB	article	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't	D000279: Administration, Cutaneous; D000328: Adult; D018687: Antidepressive Agents, Second-Generation; D016642: Bupropion; D003692: Delayed-Action Preparations; D004359: Drug Therapy, Combination; D005260: Female; D006801: Humans; D008297: Male; D009538: Nicotine; D016540: Smoking Cessation; D013375: Substance Withdrawal Syndrome; D015430: Weight Gain	None	None	https://openalex.org/W2312609348
2	False	Effects of methylphenidate on complex cognitive processing in attention-deficit hyperactivity disorder.	Three experiments were conducted to explore the effects of methylphenidate (MPH), attention-deficit hyperactivity disorder (ADHD) diagnosis, and age on performance on a complex visual-memory search task. Results showed that the effects of MPH varied with information load. On low-processing loads, all doses of MPH helped children with ADHD to improve accuracy with no cost to reaction time (RT), whereas on high loads, higher MPH doses improved error rates while slowing RT. Without medication, children with ADHD showed high error rates and slow RTs across both low and high loads, as did younger, normal control children. Because MPH slowed performance on only the most difficult, high-load conditions, it is argued that the drug improves self-regulatory ability, enabling children with ADHD to adapt differentially to high and low loads.	Berman T	1999	J Abnorm Psychol	https://doi.org/10.1037/0021-843x.108.1.90	10066996	Berman T; Douglas VI; Barr RG	article	D016430: Clinical Trial; D018848: Controlled Clinical Trial; D016428: Journal Article; D013485: Research Support, Non-U.S. Gov't	D000293: Adolescent; D000367: Age Factors; D001289: Attention Deficit Disorder with Hyperactivity; D000697: Central Nervous System Stimulants; D002648: Child; D003071: Cognition; D004305: Dose-Response Relationship, Drug; D005260: Female; D006801: Humans; D008297: Male; D008568: Memory; D008774: Methylphenidate; D011597: Psychomotor Performance; D011930: Reaction Time; D014796: Visual Perception	None	None	https://openalex.org/W2022904832
3	False	Spinal Clonidine Prolongs Labor Analgesia from Spinal Sufentanil and Bupivacaine	We sought to determine whether spinal clonidine 50 [micro sign]g prolongs the analgesia from the spinal administration of sufentanil 7.5 [micro sign]g and bupivacaine 2.5 mg early in the first stage of labor. Thirty patients were randomized to receive a 2-mL spinal injection of sufentanil 7.5 [micro sign]g + bupivacaine 2.5 mg with or without clonidine 50 [micro sign]g using a combined spinal-epidural (CSE) technique. Pain, nausea, pruritus, sedation, motor block, blood pressure, and heart rate were assessed until the patient requested additional analgesia. Analgesia was significantly prolonged in patients who received spinal sufentanil + bupivacaine + clonidine (197 +/- 70 vs 132 +/- 39 min; P = 0.004). Pain scores and side effects, including motor block, sedation, and hypotension, were similar between groups. Spinal clonidine significantly prolongs labor analgesia from spinal sufentanil and bupivacaine without producing serious adverse side effects. Implications: We studied the effects of spinal clonidine administered with spinal sufentanil and bupivacaine on labor analgesia using a combined spinal-epidural technique and conclude that spinal clonidine significantly prolongs labor analgesia from spinal sufentanil and bupivacaine without producing serious adverse effects. (Anesth Analg 1999;88:573-76)	D'Angelo R	1999	Anesth Analg	https://doi.org/10.1097/00000539-199903000-00020	10072008	D'Angelo R; Evans E; Dean LA; Gaver R; Eisenach JC	article	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial	D000328: Adult; D016362: Analgesia, Obstetrical; D000700: Analgesics; D000701: Analgesics, Opioid; D000779: Anesthetics, Local; D002045: Bupivacaine; D003000: Clonidine; D004357: Drug Synergism; D004359: Drug Therapy, Combination; D005260: Female; D006801: Humans; D007278: Injections, Spinal; D017409: Sufentanil	None	None	https://openalex.org/W2021097359
4	False	Low-Dose Clozapine for the Treatment of Drug-Induced Psychosis in Parkinson's Disease	Drug-induced psychosis is a difficult problem to manage in patients with Parkinson's disease. Multiple open-label studies have reported that treatment with clozapine at low doses ameliorates psychosis without worsening parkinsonism.We conducted a randomized, double-blind, placebo-controlled trial of low doses of clozapine (6.25 to 50 mg per day) in 60 patients at six sites over a period of 14 months. The patients (mean age, 72 years) had idiopathic Parkinson's disease and drug-induced psychosis of at least four weeks' duration. All the patients continued to receive fixed doses of antiparkinsonian drugs during the four weeks of the trial. Blood counts were monitored weekly in all the patients.The mean dose of clozapine was 24.7 mg per day. The patients in the clozapine group had significantly more improvement than those in the placebo group in all three of the measures used to determine the severity of psychosis. The mean (+/-SE) scores on the Clinical Global Impression Scale improved by 1.6+/-0.3 points for the patients receiving clozapine, as compared with 0.5+/-0.2 point for those receiving placebo (P<0.001). The score on the Brief Psychiatric Rating Scale improved by 9.3+/-1.5 points for the patients receiving clozapine, as compared with 2.6+/-1.3 points for those receiving placebo (P=0.002). The score on the Scale for the Assessment of Positive Symptoms improved by 11.8+/-2.0 points for the patients receiving clozapine, as compared with 3.8+/-1.9 points for those receiving placebo (P=0.01). Seven patients treated with clozapine had an improvement of at least three on the seven-point Clinical Global Impression Scale, as compared with only one patient given placebo. Clozapine treatment improved tremor and had no deleterious effect on the severity of parkinsonism. In one patient, clozapine was discontinued because of leukopenia.Clozapine, at daily doses of 50 mg or less, is safe and significantly improves drug-induced psychosis without worsening parkinsonism.	Parkinson Study Group	1999	N Engl J Med	https://doi.org/10.1056/nejm199903113401003	10072410	Parkinson Study Group	article	D016430: Clinical Trial; D016428: Journal Article; D016448: Multicenter Study; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't; D013487: Research Support, U.S. Gov't, P.H.S.	D000368: Aged; D000978: Antiparkinson Agents; D014150: Antipsychotic Agents; D003024: Clozapine; D004311: Double-Blind Method; D005260: Female; D006801: Humans; D008297: Male; D010300: Parkinson Disease; D011605: Psychoses, Substance-Induced; D016896: Treatment Outcome	None	None	https://openalex.org/W4239283954
5	False	Predictors of Relapse Following Response From a First Episode of Schizophrenia or Schizoaffective Disorder	Background:We examined relapse after response to a first episode of schizophrenia or schizoaffective disorder.Methods: Patients with first-episode schizophrenia were assessed on measures of psychopathologic variables, cognition, social functioning, and biological variables and treated according to a standardized algorithm.The sample for the relapse analyses consisted of 104 patients who responded to treatment of their index episode and were at risk for relapse.Results: Five years after initial recovery, the cumulative first relapse rate was 81.9% (95% confidence interval [CI], 70.6%-93.2%);the second relapse rate was 78.0% (95% CI, 46.5%-100.0%).By 4 years after recovery from a second relapse, the cumulative third relapse rate was 86.2% (95% CI, 61.5%-100.0%).Discontinuing antipsychotic drug therapy increased the risk of relapse by almost 5 times (hazard ratio for an initial relapse, 4.89 [99% CI, 2.49-9.60];hazard ratio for a second relapse, 4.57 [99% CI, 1.49-14.02]).Subsequent analyses controlling for antipsychotic drug use showed that patients with poor premorbid adaptation to school and premorbid social withdrawal relapsed earlier.Sex, diagnosis, obstetric complications, duration of psychotic illness before treatment, baseline symptoms, neuroendocrine measures, methylphenidate hydrochloride challenge response, neuropsychologic and magnetic resonance imaging measures, time to response of the initial episode, adverse effects during treatment, and presence of residual symptoms after the initial episode were not significantly related to time to relapse. Conclusions:There is a high rate of relapse within 5 years of recovery from a first episode of schizophrenia and schizoaffective disorder.This risk is diminished by maintenance antipsychotic drug treatment.	Robinson D	1999	Arch Gen Psychiatry	https://doi.org/10.1001/archpsyc.56.3.241	10078501	Robinson D; Woerner MG; Alvir JM; Bilder R; Goldman R; Geisler S; Koreen A; Sheitman B; Chakos M; Mayerhoff D; Lieberman JA	article	D016428: Journal Article; D013485: Research Support, Non-U.S. Gov't; D013487: Research Support, U.S. Gov't, P.H.S.	D000293: Adolescent; D000328: Adult; D014150: Antipsychotic Agents; D015331: Cohort Studies; D005260: Female; D005476: Fluphenazine; D005500: Follow-Up Studies; D006212: Hallucinations; D006801: Humans; D008137: Longitudinal Studies; D008279: Magnetic Resonance Imaging; D009483: Neuropsychological Tests; D010349: Patient Compliance; D011247: Pregnancy; D011248: Pregnancy Complications; D011336: Probability; D011569: Psychiatric Status Rating Scales; D011618: Psychotic Disorders; D012307: Risk Factors; D012559: Schizophrenia; D012565: Schizophrenic Psychology; D055502: Secondary Prevention; D012720: Severity of Illness Index; D012737: Sex Factors; D016896: Treatment Outcome	None	None	https://openalex.org/W2154849243
6	False	Comparison of Risperidone and Placebo for Psychosis and Behavioral Disturbances Associated With Dementia	We report the findings from the first large, double-blind, placebo-controlled study conducted to evaluate the efficacy and safety of risperidone in the treatment of psychotic and behavioral symptoms in institutionalized elderly patients with dementia.625 patients (67.8% women; mean age = 82.7 years) with DSM-IV diagnoses of Alzheimer's disease (73%), vascular dementia (15%), or mixed dementia (12%) and significant psychotic and behavioral symptoms were included. Each patient was randomly assigned to receive placebo or 0.5 mg/day, 1 mg/day, or 2 mg/day of risperidone for 12 weeks. The primary outcome measure was the Behavioral Pathology in Alzheimer's Disease rating scale (BEHAVE-AD).The study was completed by 70% of the patients. Baseline Functional Assessment Staging scores were 6 or 7 in more than 95% of the patients, indicating severe dementia. At endpoint, significantly greater reductions in BEHAVE-AD total scores and psychosis and aggressiveness subscale scores were seen in patients receiving 1 and 2 mg/day of risperidone than in placebo patients (p = .005 and p < .001, respectively). At week 12, 0.5 mg/day of risperidone was superior to placebo in reducing BEHAVE-AD aggression scores (p = .02). More adverse events were reported by patients receiving 2 mg/day of risperidone than 1 mg/day. The most common dose-related adverse events were extrapyramidal symptoms, somnolence, and mild peripheral edema. The frequency of extrapyramidal symptoms in patients receiving 1 mg/day of risperidone was not significantly greater than in placebo patients.Risperidone significantly improved symptoms of psychosis and aggressive behavior in patients with severe dementia. Results show that 1 mg/day of risperidone is an appropriate dose for most elderly patients with dementia.	Katz IR	1999	J Clin Psychiatry	https://doi.org/10.4088/jcp.v60n0207	10084637	Katz IR; Jeste DV; Mintzer JE; Clyde C; Napolitano J; Brecher M	article	D016430: Clinical Trial; D003160: Comparative Study; D016428: Journal Article; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't	D000368: Aged; D000369: Aged, 80 and over; D000374: Aggression; D000544: Alzheimer Disease; D014150: Antipsychotic Agents; D001480: Basal Ganglia Diseases; D003704: Dementia; D015140: Dementia, Vascular; D004305: Dose-Response Relationship, Drug; D004311: Double-Blind Method; D004334: Drug Administration Schedule; D005260: Female; D015577: Geriatric Assessment; D006801: Humans; D007326: Institutionalization; D008297: Male; D010919: Placebos; D018967: Risperidone; D012720: Severity of Illness Index; D016896: Treatment Outcome	None	None	https://openalex.org/W1993818042
7	False	THA Improves Word Priming and Clonidine Enhances Fluency and Working Memory in Alzheimer's Disease	We investigated the effects of a single administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA, 25 and 50 mg, orally), and an α2-agonist, clonidine (0.5 and 2 μg/kg, orally), on neuropsychologic performance in two groups of patients with Alzheimer's disease (AD). Clonidine enhanced a spatial working memory and verbal fluency, but had no effect on spatial span or word priming. THA enhanced word priming, but had no effect on other performance measures. Our data suggests that degeneration of the LC noradrenergic system and the cholinergic cells of the basal forebrain have different functional consequences during the progression of AD. Finally, a combined treatment with noradrenergic and cholinergic drugs might produce a qualitatively broader effect on cognitive functions than either of the treatments alone, and more effectively attenuate clinical dementia.	Riekkinen P	1999	Neuropsychopharmacology	https://doi.org/10.1016/s0893-133x(98)00093-1	10088136	Riekkinen P; Riekkinen M	article	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial	D000316: Adrenergic alpha-Agonists; D000368: Aged; D000544: Alzheimer Disease; D001794: Blood Pressure; D003000: Clonidine; D004311: Double-Blind Method; D004359: Drug Therapy, Combination; D005260: Female; D006801: Humans; D008297: Male; D008570: Memory, Short-Term; D018697: Nootropic Agents; D011597: Psychomotor Performance; D013619: Tacrine; D014705: Verbal Behavior	None	None	https://openalex.org/W1561544516
8	False	Diuretics and β-Blockers Do Not Have Adverse Effects at 1 Year on Plasma Lipid and Lipoprotein Profiles in Men With Hypertension	Concern based on the reported short-term adverse effects of antihypertensive agents on plasma lipid and lipoprotein profiles (PLPPs) has complicated the therapy for hypertension.To compare the long-term (1-year) effects of 6 different antihypertensive drugs and placebo on PLPPs in a multicenter, randomized, double-blind, parallel-group clinical trial in 15 US Veterans Affairs medical centers.A total of 1292 ambulatory men, 21 years or older, with diastolic blood pressures (DBPs) ranging from 95 to 109 mm Hg taking placebo were randomized to receive placebo or 1 of 6 antihypertensive drugs: hydrochlorothiazide, atenolol, captopril, clonidine, diltiazem, or prazosin. After drug titration, patients with a DBP of less than 90 mm Hg were followed up for 1 year. Plasma lipids and lipoprotein profiles were determined at baseline, after initial titration, and at 1 year.After 8 weeks on a regimen of hydrochlorothiazide, increases of 3.3 mg/dL (0.09 mmol/L) in total cholesterol and 2.7 mg/dL in apolipoprotein B were significantly different (P< or =.05) from decreases of 9.3 mg/dL in total cholesterol and 5.4 mg/dL in ApoB levels while receiving prazosin but not from placebo. Patients achieving positive DBP control using hydrochlorothiazide (responders) showed no adverse changes in PLPPs, whereas nonresponders exhibited increases in triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels. Plasma lipids and lipoprotein profiles did not change significantly among treatment groups after 1 year except for minor decreases in high-density lipoprotein 2 levels using hydrochlorothiazide, clonidine, and atenolol.None of these 6 antihypertensive drugs has any long-term adverse effects on PLPPs and, therefore, may be safely prescribed. Previously reported short-term adverse effects from using hydrochlorothiazide are limited to nonresponders.	Lakshman MR	1999	Arch Intern Med	https://doi.org/10.1001/archinte.159.6.551	10090111	Lakshman MR; Reda DJ; Materson BJ; Cushman WC; Freis ED	article	D016430: Clinical Trial; D003160: Comparative Study; D016428: Journal Article; D016448: Multicenter Study; D016449: Randomized Controlled Trial; D013486: Research Support, U.S. Gov't, Non-P.H.S.	D000319: Adrenergic beta-Antagonists; D000328: Adult; D000368: Aged; D000959: Antihypertensive Agents; D001262: Atenolol; D001786: Blood Glucose; D002216: Captopril; D003000: Clonidine; D004110: Diltiazem; D004232: Diuretics; D004311: Double-Blind Method; D006787: Hospitals, Veterans; D006801: Humans; D006852: Hydrochlorothiazide; D006973: Hypertension; D008055: Lipids; D008074: Lipoproteins; D008297: Male; D008875: Middle Aged; D011188: Potassium; D011224: Prazosin; D013997: Time Factors; D016896: Treatment Outcome; D014481: United States	None	None	https://openalex.org/W2095656324
9	False	Selegiline-induced postural hypotension in Parkinson's disease: A longitudinal study on the effects of drug withdrawal	The United Kingdom Parkinson's Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinson's disease (PD) randomized to receive 10 mg selegiline per day and L-dopa compared with those taking L-dopa alone. Recently, we found that therapy with selegiline and L-dopa was associated with selective systolic orthostatic hypotension which was abolished by withdrawal of selegiline. This unwanted effect on postural blood pressure was not the result of underlying autonomic failure. The aims of this study were to confirm our previous findings in a separate cohort of patients and to determine the time course of the cardiovascular consequences of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension.The cardiovascular responses to standing and head-up tilt were studied repeatedly in PD patients receiving selegiline and as the drug was withdrawn.Head-up tilt caused systolic orthostatic hypotension which was marked in six of 20 PD patients on selegiline, one of whom lost consciousness with unrecordable blood pressures. A lesser degree of orthostatic hypotension occurred with standing. Orthostatic hypotension was ameliorated 4 days after withdrawal of selegiline and totally abolished 7 days after discontinuation of the drug. Stopping selegiline also significantly reduced the supine systolic and diastolic blood pressures consistent with a previously undescribed supine pressor action.This study confirms our previous finding that selegiline in combination with L-dopa is associated with selective orthostatic hypotension. The possibilities that these cardiovascular findings might be the result of non-selective inhibition of monoamine oxidase or of amphetamine and metamphetamine are discussed.	Churchyard A	1999	Mov Disord	https://doi.org/10.1002/1531-8257(199903)14:2<246::aid-mds1008>3.0.co;2-p	10091617	Churchyard A; Mathias CJ; Lees AJ	article	D016430: Clinical Trial; D016428: Journal Article	D000368: Aged; D000704: Analysis of Variance; D000978: Antiparkinson Agents; D001794: Blood Pressure; D004244: Dizziness; D004359: Drug Therapy, Combination; D004837: Epinephrine; D005260: Female; D006257: Head; D006339: Heart Rate; D006801: Humans; D007024: Hypotension, Orthostatic; D008297: Male; D008875: Middle Aged; D009638: Norepinephrine; D010300: Parkinson Disease; D011187: Posture; D011446: Prospective Studies; D012642: Selegiline; D012720: Severity of Illness Index; D013375: Substance Withdrawal Syndrome; D013997: Time Factors	None	None	https://openalex.org/W2062309915

	include	title	abstract	first_author	year	journal	doi	pubmed_id	authors	pubmed_type	publication_types	mesh	webofscience_id	central_id	openalex_id
841	False	THE ANTIPSYCHOTICS	Antipsychotics are medications that reduce the symptoms of hallucinations and delusions that characterize psychosis. They have been used in the treatment of patients with schizophrenia for more than 45 years.48 Fourteen antipsychotics are currently marketed in the United States. Ten are considered “typical” antipsychotics. The “typical” antipsychotics are all equally effective in their ability to reduce symptoms of psychosis. Because adolescents with a psychotic illness are often treated with doses of antipsychotics similar to those used in adults, a listing of these medications and their dosing in adults with psychotic disorders is shown in Table 1. More recently, four agents considered “atypical” antipsychotics became available. What distinguishes the typical from the atypical antipsychotics is that atypical antipsychotics are associated with a reduced or absent risk for extrapyramidal side effects (EPSs).119 A list of these medications and their usual daily dosing for adults with schizophrenia are shown in Table 2. Other than the 14 agents that are marketed for use in psychotic disorders, two other medications with antipsychotic properties are currently marketed for neuropsychiatric illnesses in the United States. Pimozide (Orap) is labeled for use for treatment-resistant Tourette syndrome, whereas amoxapine (Asendin) is marketed as an antidepressant. As can be seen from Tables 1 and 2, daily doses of antipsychotics (in mg) generally used to treat schizophrenia in adults vary widely between compounds. Medications that are generally administered in larger daily doses (in mg) are considered “low-potency” agents (e.g., chlorpromazine, thioridazine, and clozapine). Similarly, medications that are generally given in smaller daily doses (in mg) are considerd “high-potency” agents (e.g., haloperidol, fluphenazine, and risperidone). As is discussed later, the distinction between high- and low-potency compounds is important when considering side effects. But “potency” does not reflect an agent's ability to reduce target symptoms of psychosis. Other than their ability to treat psychotic illnesses, what the antipsychotic medications also have in common is that they all reversibly block type 2 dopamine (D2) receptors in the central nervous system. As can be seen in Tables 1 and 2, the usual daily dosing for antipsychotics in adults with psychotic disorders is generally related to each medication's ability to block D2 receptors. Specifically, drugs with greater affinity for D2 receptors are generally more potent than those with lower D2 receptor affinity.53, 141, 151, 152 This finding led to the view that D2 receptor blockade was pivotal for the treatment of psychosis.119 At therapeutic doses, all antipsychotics bind to other receptors in the central nervous system to varying degrees. These include muscarinic, α-adrenergic (both α1 and α2), histaminergic (H1) receptors, and several serotonin receptors. As is discussed later, an antipsychotic's blockade of these other receptors causes some of the side effects seen with each agent at therapeutic doses.26, 152	Findling RL	1998	Pediatr Clin North Am	https://doi.org/10.1016/s0031-3955(05)70070-5	9884683	Findling RL; Schulz SC; Reed MD; Blumer JL	article	D016428: Journal Article; D013485: Research Support, Non-U.S. Gov't; D013487: Research Support, U.S. Gov't, P.H.S.; D016454: Review	D000293: Adolescent; D000328: Adult; D000367: Age Factors; D014150: Antipsychotic Agents; D002648: Child; D002659: Child Development Disorders, Pervasive; D019955: Conduct Disorder; D006801: Humans; D019964: Mood Disorders; D018579: Patient Selection; D010372: Pediatrics; D010554: Personality Disorders; D013981: Tic Disorders	None	None	https://openalex.org/W1520140903
842	False	Olanzapine Versus Haloperidol Treatment in First-Episode Psychosis	It has been hypothesized that the morbidity and mortality associated with schizophrenia can be prevented by providing effective treatment during the first episode of psychosis. Hence, the authors examined patients with first-episode psychosis to determine the efficacy and safety of olanzapine and haloperidol treatment.A subpopulation of first-episode patients (N=83) from a large prospective, multicenter, international, double-blind, 6-week acute treatment study was evaluated. These patients were selected from a pool of 1,996 patients who had a DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder and who also met the following criteria: 1) the length of their current psychotic episode had to be 5 or fewer years, and 2) patients had to be 45 years of age or younger at onset of first psychotic symptoms.Compared to haloperidol, olanzapine showed a statistically significantly greater reduction in the Brief Psychiatric Rating Scale (BPRS) total and negative scores and in the Positive and Negative Syndrome Scale total and positive scores. Clinical response (defined as 40% or greater improvement in BPRS total score from baseline) was also statistically significantly higher in olanzapine-treated patients (67.2%) than in haloperidol-treated patients (29.2%). Olanzapine-treated patients further showed statistically significant improvements in the Simpson-Angus scale and Barnes Akathisia Scale scores, while haloperidol-treated patients showed a worsening on both measures. Compared to olanzapine-treated multiple-episode patients in the parent study, olanzapine-treated first-episode patients achieved an even statistically significantly higher response. Haloperidol-treated first-episode patients experienced statistically significantly more extrapyramidal symptoms than haloperidol-treated multiple-episode patients.In patients experiencing first-episode psychosis, olanzapine had a risk-benefit profile significantly superior to that of haloperidol. The study results suggest that novel antipsychotic agents such as olanzapine should be considered as a preferred option in first-episode psychosis, on the basis of both safety and efficacy advantages.	Sanger TM	1999	Am J Psychiatry	https://doi.org/10.1176/ajp.156.1.79	9892301	Sanger TM; Lieberman JA; Tohen M; Grundy S; Beasley C; Tollefson GD	article	D016430: Clinical Trial; D003160: Comparative Study; D016428: Journal Article; D016448: Multicenter Study; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't	D017668: Age of Onset; D014150: Antipsychotic Agents; D001480: Basal Ganglia Diseases; D001569: Benzodiazepines; D010054: Brief Psychiatric Rating Scale; D004311: Double-Blind Method; D006220: Haloperidol; D006801: Humans; D000077152: Olanzapine; D010890: Pirenzepine; D011446: Prospective Studies; D011618: Psychotic Disorders; D012559: Schizophrenia; D012565: Schizophrenic Psychology; D012720: Severity of Illness Index; D013997: Time Factors; D016896: Treatment Outcome	None	None	https://openalex.org/W1971880978
843	False	Effect of Clozapine and Adjunctive High-Dose Glycine in Treatment-Resistant Schizophrenia	OBJECTIVE: The focus of this study was the systematic evaluation of the clinical effects of glycine as an adjunct to the atypical antipsychotic clozapine in the treatment of schizophrenia. METHOD: In a double-blind, placebo-controlled study, 19 patients with chronic, treatment-resistant schizophrenia who were maintained on optimal doses of clozapine (400–1200 mg/day) were administered either 30 g/day of glycine (N=9) or placebo (N=10) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, and the Simpson-Angus movement scale were completed biweekly. RESULTS: The use of glycine as an adjunct to clozapine was not effective in decreasing positive or negative symptoms. In contrast, the patients treated with clozapine without glycine had a 35% reduction in positive symptoms. CONCLUSIONS: These preliminary data suggest that glycine may interfere with the antipsychotic efficacy of atypical neuroleptics such as clozapine.	Potkin SG	1999	Am J Psychiatry	https://doi.org/10.1176/ajp.156.1.145	9892314	Potkin SG; Jin Y; Bunney BG; Costa J; Gulasekaram B	article	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial	D000328: Adult; D014150: Antipsychotic Agents; D010054: Brief Psychiatric Rating Scale; D003024: Clozapine; D004359: Drug Therapy, Combination; D005260: Female; D005998: Glycine; D006801: Humans; D008297: Male; D010919: Placebos; D012559: Schizophrenia; D012565: Schizophrenic Psychology; D016896: Treatment Outcome	None	None	https://openalex.org/W2072365144
844	False	Order of onset of substance abuse and depression in a sample of depressed outpatients	Drug abuse has been thought to cause depression, or to serve as a form of self-medication for depression. Our objective was to examine whether specific types of drug abuse preceded or followed the onset of depression. A retrospective, blinded case-controlled assessment of the drug and depressive history of depressed outpatients was conducted. Three hundred seventy-five patients with major depressive disorder were evaluated for comorbid drug dependence using the Structured Clinical Interview for DSM-III-R (SCID). They were selected from the psychiatric outpatient department of a metropolitan teaching hospital and grouped into homogeneous classes of drug dependence including alcohol, cannabis, cocaine, amphetamine, LSD, hypnosedative, opiate, and polysubstance use. We determined the percent of depressed patients with each specific type of drug abuse, their age of onset of depression and onset of specific drug abuse, and the mean number of lifetime depressive episodes for each patient. We found that alcohol dependence followed the onset of first life depression by 4.7 years (P = .02, two-tailed). Among polydrug-dependent patients, each drug abused followed the onset of depression, except for LSD, which coincided with the onset of depression. Among polydrug users, cocaine dependence occurred 6.8 years after the first major depressive episode (P = .007) and alcohol dependence 4.5 years after the onset of depression (P = .007). Opiate and sedative users had the least number of lifetime depressive episodes (3.7), and LSD and cocaine users had the greatest number (12.2). We conclude that alcohol and cocaine use in this sample of depressed outpatients conformed to a pattern of self-medication.	Abraham HD	1999	Compr Psychiatry	https://doi.org/10.1016/s0010-440x(99)90076-7	9924877	Abraham HD; Fava M	article	D016428: Journal Article; D013485: Research Support, Non-U.S. Gov't; D013487: Research Support, U.S. Gov't, P.H.S.	D000328: Adult; D017668: Age of Onset; D000428: Alcohol Drinking; D000704: Analysis of Variance; D015984: Causality; D015331: Cohort Studies; D015897: Comorbidity; D003430: Cross-Sectional Studies; D003866: Depressive Disorder; D006801: Humans; D013287: Illicit Drugs; D008297: Male; D008404: Massachusetts; D008875: Middle Aged; D016017: Odds Ratio; D012651: Self Medication; D019966: Substance-Related Disorders	None	None	https://openalex.org/W2058947119
845	False	Combination treatment with clozapine and paroxetine in schizophrenia: safety and tolerability data from a prospective open clinical trial	Clozapine is a drug with many side effects, some of them with potentially hazardous outcome (e.g. seizures, agranulocytosis), if not carefully monitored. It has been shown that the metabolism of clozapine may be affected by concomitant treatment with selective serotonin reuptake inhibitors (SSRIs), while there have been reports of improved efficacy on negative symptomatology of clozapine in combination with SSRIs. Therefore, this prospective open clinical trial was performed to investigate the safety and tolerability of the coadministration of clozapine and paroxetine under control of serum concentrations of clozapine and its metabolites and the effect of this combination treatment on psychopathological outcome was evaluated. A total of 14 patients suffering from schizophrenia or schizodepressive disorder with predominant negative symptomatology were included. The duration of the study was at least 6 weeks for each patient. Initial treatment was a monotherapy with clozapine at a daily dose of 2.5 mg/kg weight. After two measurements of serum concentrations of clozapine and metabolites during steady state conditions, an add-on therapy with 20 mg paroxetine was initiated. No concomitant medication was allowed. The main finding of our prospective study was that addition of paroxetine to a monotherapy with clozapine was a well tolerated medication that did not give rise to new clinically relevant side effects. After addition of paroxetine the serum concentrations of clozapine and its major metabolites remained virtually constant. The results of the psychopathological measurements indicated a further clinical improvement, although the small open study could not test for efficacy.	Anghelescu I	1998	Eur Neuropsychopharmacol	https://doi.org/10.1016/s0924-977x(97)00093-x	9928923	Anghelescu I; Szegedi A; Schlegel S; Weigmann H; Hiemke C; Wetzel H	article	D016430: Clinical Trial; D018848: Controlled Clinical Trial; D016428: Journal Article	D000328: Adult; D014150: Antipsychotic Agents; D003024: Clozapine; D004359: Drug Therapy, Combination; D005260: Female; D006801: Humans; D008297: Male; D017374: Paroxetine; D011446: Prospective Studies; D012559: Schizophrenia; D017367: Selective Serotonin Reuptake Inhibitors	None	None	https://openalex.org/W2014489054
846	False	Prolactin Levels and Adverse Events in Patients Treated with Risperidone	Hyperprolactinemia is a common clinical disorder that may lead to sexual dysfunction or galactorrhea.It may arise from a variety of etiologies, including the use of antipsychotic agents, presumably because of a dopamine receptor blockade. This analysis was designed to characterize the relationship between risperidone, serum prolactin levels, and possible clinical sequelae. All data from randomized, double-blind studies of risperidone in patients with chronic schizophrenia were analyzed. The two largest studies (the North American and multinational trials) included 841 patients (259 women, 582 men) with paired prolactin level data and 1,884 patients (554 women, 1,330 men) with data on six adverse events possibly associated with increased prolactin levels (amenorrhea, galactorrhea, and decreased libido in women; erectile dysfunction, ejaculatory dysfunction, gynecomastia, and decreased libido in men). Both risperidone and haloperidol produced dose-related increases in plasma prolactin levels in men and women. Among women, the risperidone dose was not correlated with adverse events, nor were the adverse events correlated with endpoint prolactin levels. Among men, the incidence of adverse events was positively correlated with risperidone dose; however, at risperidone doses of 4 to 10 mg/day the incidence of adverse events was not significantly higher than that observed in patients receiving placebo. Furthermore, adverse events in men were unrelated to plasma prolactin levels. Risperidone-associated increase in serum prolactin levels was not significantly correlated to the emergence of possible prolactin-related side effects. (J Clin Psychopharmacol 1999;19:57-61)	Kleinberg DL	1999	J Clin Psychopharmacol	https://doi.org/10.1097/00004714-199902000-00011	9934944	Kleinberg DL; Davis JM; de Coster R; Van Baelen B; Brecher M	article	D016428: Journal Article	D000328: Adult; D014150: Antipsychotic Agents; D005260: Female; D005687: Galactorrhea; D006801: Humans; D008297: Male; D011388: Prolactin; D016032: Randomized Controlled Trials as Topic; D012189: Retrospective Studies; D018967: Risperidone; D012559: Schizophrenia; D012727: Sex Characteristics	None	None	https://openalex.org/W2015837785
847	False	Dexmedetomidine Failed to Block the Acute Hyperdynamic Response to Electroconvulsive Therapy	Orally administered clonidine (0.2-0.3 mg) has been reported to decrease the acute hypertensive response to electroconvulsive therapy (ECT) without prolonging early recovery. This preliminary study was designed to evaluate the acute hemodynamic effects of the investigational alpha2-adrenergic agonist, dexmedetomidine, in patients undergoing a series of ECT treatments.Six patients undergoing a series of three to six consecutive ECT treatments were studied according to a randomized, double-blind, placebo-controlled protocol All patients received either saline or dexmedetomidine, 0.5 or 1.0 microg/kg intravenously, 10-30 min before induction of anesthesia for ECT using a standardized anesthesia protocol. In addition to assessing the cardiovascular variables, the duration of seizure activity, degree of sedation, and time to discharge from the Phase I recovery unit were assessed.Although dexmedetomidine produced dose-related increases in the level of sedation before the ECT procedure, it failed to decrease the peak blood pressure and heart rate responses after the ECT treatment. The 0.5 and 1.0 microg/kg doses of dexmedetomidine prolonged the times to orientation and to discharge from the Phase I unit.The results of this pilot study suggest that dexmedetomidine (0.5-1.0 microg/kg given intravenously) is not beneficial in controlling the acute hyperdynamic response after ECT.	Fu W	1999	Anesthesiology	https://doi.org/10.1097/00000542-199902000-00015	9952147	Fu W; White PF	article	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial; D013485: Research Support, Non-U.S. Gov't	D000368: Aged; D018712: Analgesics, Non-Narcotic; D001794: Blood Pressure; D003866: Depressive Disorder; D004311: Double-Blind Method; D004565: Electroconvulsive Therapy; D006801: Humans; D006973: Hypertension; D006993: Hypnotics and Sedatives; D007093: Imidazoles; D020926: Medetomidine; D008875: Middle Aged	None	None	https://openalex.org/W2033537367
848	False	A Double‐Blind, Placebo‐Controlled, Ascending‐Dose Evaluation of the Pharmacokinetics and Tolerability of Modafinil Tablets in Healthy Male Volunteers	A randomized, double‐blind, placebo‐controlled, ascending‐dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7‐day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady‐state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of ∼50 mL/min, a volume of distribution of ∼0.8 L/kg, and a long half‐life of ∼15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d‐ modafinil enantiomer was eliminated at a threefold faster rate than l‐ modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg .	Wong YN	1999	J Clin Pharmacol	https://doi.org/10.1177/00912709922007534	9987698	Wong YN; Simcoe D; Hartman LN; Laughton WB; King SP; McCormick GC; Grebow PE	article	D016430: Clinical Trial; D016428: Journal Article; D016449: Randomized Controlled Trial	D000293: Adolescent; D000328: Adult; D001007: Anxiety; D019540: Area Under Curve; D001559: Benzhydryl Compounds; D000697: Central Nervous System Stimulants; D003627: Data Interpretation, Statistical; D004305: Dose-Response Relationship, Drug; D004311: Double-Blind Method; D006261: Headache; D006801: Humans; D008297: Male; D008657: Metabolic Clearance Rate; D008875: Middle Aged; D000077408: Modafinil; D007319: Sleep Initiation and Maintenance Disorders; D013237: Stereoisomerism; D013607: Tablets; D013610: Tachycardia	None	None	https://openalex.org/W2102196985
849	False	Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials	The objective of this meta-analysis is to summarize the efficacy and tolerability of the new antipsychotics risperidone, olanzapine, sertindole and quetiapine in schizophrenia compared to placebo and conventional antipsychotics. The main results are: (1) All of the 4 new drugs are more effective than placebo, but the magnitude of the effect is only moderate [mean effect size, r, of all antipsychotics vs. placebo=0.25, with a 95% confidence interval (CI)=0.22–0.28, n=2477]. (2) According to the studies published to date, sertindole and quetiapine are as effective as haloperidol, and risperidone and olanzapine are slightly more effective than haloperidol in the treatment of global schizophrenic symptomatology. (3) With respect to negative symptoms, all new antipsychotics are more effective than placebo. However, contrary to widespread opinion, so is the `conventional' antipsychotic haloperidol. Risperidone and olanzapine are slightly superior, sertindole is as effective and—according to the only study fully published to date—quetiapine is even slightly less effective than haloperidol in this regard. (4) All new antipsychotics are associated with less frequent use of antiparkinson medication than haloperidol, with risperidone appearing to have a slightly less favourable EPS-profile than the other new antipsychotics. The methodological limitations of this review, the generalizability of the results and expectations from future research are discussed.	Leucht S	1999	Schizophr Res	https://doi.org/10.1016/s0920-9964(98)00105-4	9988841	Leucht S; Pitschel-Walz G; Abraham D; Kissling W	article	D003160: Comparative Study; D016428: Journal Article; D017418: Meta-Analysis	D014150: Antipsychotic Agents; D001480: Basal Ganglia Diseases; D001569: Benzodiazepines; D003987: Dibenzothiazepines; D004311: Double-Blind Method; D006220: Haloperidol; D006801: Humans; D007093: Imidazoles; D007211: Indoles; D000077152: Olanzapine; D010890: Pirenzepine; D000069348: Quetiapine Fumarate; D016032: Randomized Controlled Trials as Topic; D018967: Risperidone; D012559: Schizophrenia	None	None	https://openalex.org/W2109481947
850	False	Clozapine and Risperidone in Chronic Schizophrenia: Effects on Symptoms, Parkinsonian Side Effects, and Neuroendocrine Response	Back to table of contents Previous article Next article Regular ArticleFull AccessClozapine and Risperidone in Chronic Schizophrenia: Effects on Symptoms, Parkinsonian Side Effects, and Neuroendocrine ResponseAlan F. Breier, M.D., Anil K. Malhotra, M.D., Tung-Ping Su, M.D., Debra A. Pinals, M.D., Igor Elman, M.D., Caleb M. Adler, M.D., R. Todd Lafargue, M.D., Allan Clifton, B.A., and David Pickar, M.D.Alan F. BreierSearch for more papers by this author, M.D., Anil K. MalhotraSearch for more papers by this author, M.D., Tung-Ping SuSearch for more papers by this author, M.D., Debra A. PinalsSearch for more papers by this author, M.D., Igor ElmanSearch for more papers by this author, M.D., Caleb M. AdlerSearch for more papers by this author, M.D., R. Todd LafargueSearch for more papers by this author, M.D., Allan CliftonSearch for more papers by this author, B.A., and David PickarSearch for more papers by this author, M.D.Published Online:1 Feb 1999https://doi.org/10.1176/ajp.156.2.294AboutSectionsView articleAbstractPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View articleAbstractOBJECTIVE: Clozapine and risperidone were the first two “second-generation” antipsychotic drugs approved for schizophrenia. There is currently little information about their comparative efficacy from head-to-head clinical trials. The purpose of this study was to examine the comparative efficacy of clozapine and risperidone for positive and negative symptoms, depression, parkinsonian side effects, and indexes of neuroendocrine function in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents. METHOD: After a baseline fluphenazine treatment period, 29 patients participated in a 6-week, double-blind, parallel-group comparison of the effects of these agents. RESULTS: Clozapine was superior to risperidone for positive symptoms and parkinsonian side effects, but there were no significant differences between the drugs on two measures of negative symptoms, Brief Psychiatric Rating Scale total scores, and depression scores. The clozapine patients, but not the risperidone patients, demonstrated significant reductions from the fluphenazine baseline in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than risperidone or fluphenazine. The mean daily doses during week 6 of the trial were 403.6 mg of clozapine and 5.9 mg of risperidone. CONCLUSIONS: The findings from this study indicate that these drugs have both important differences and similarities in their comparative efficacy in chronically ill, partially responsive patients with schizophrenia. Further research on second-generation antipsychotic drugs in this patient population that addresses key methodological issues, such as optimal dose and treatment duration, are needed. Clozapine and risperidone were the first two antipsychotic drugs of a new class of agents for the pharmacotherapy of schizophrenia. This class, which also includes olanzapine, sertindole, quetiapine, and ziprasidone, is distinguished from the typical neuroleptic agents by producing clinical efficacy with low levels of parkinsonian side effects or none. Although clozapine and risperidone were approved by the Food and Drug Administration in 1989 and 1993, respectively, and are now used worldwide, there are relatively few data from head-to-head clinical trials that have assessed their effects on symptoms, side effects, and neuroendocrine parameters in patients with schizophrenia. Thus, basic questions pertaining to their comparative efficacy remain unanswered.It is reasonable to predict differences in clinical efficacy between clozapine and risperidone because they have some striking differences in their neurochemical properties and their effects in animal models. Even though both agents have a higher serotonin 5-HT2A-to-dopamine D2 binding ratio—a characteristic shared by the new-generation antipsychotics (1)—clozapine has two orders of magnitude lower affinity for dopamine D2 receptors and substantially lower affinity for 5-HT2A receptors than risperidone (2–4). In addition, clozapine has severalfold greater antimuscarinic and antihistaminergic effects than risperidone (2). In a primate model of acute dystonia, clozapine had essentially no associated dystonia, whereas risperidone exhibited dose-dependent effects (5). Last, in clinically recommended doses, clozapine appears not to elevate plasma prolactin levels; the data on risperidone’s effects on prolactin are inconclusive (6, 7). Lack of prolactin effects is a parameter proposed for defining the “atypical” profile of second-generation antipsychotic drugs (8).Given the interest in clozapine and risperidone, we decided to undertake a study of the comparative efficacy of these drugs for positive and negative symptoms, depression, parkinsonian symptoms, and neuroendocrine indexes in schizophrenic patients who met a priori criteria for partial response to traditional neuroleptic agents.METHODPatients who participated in this study were enrolled in the Section on Clinical Studies treatment program at the National Institutes of Health Clinical Center, Bethesda, Md. Patients met the DSM-IV criteria for chronic schizophrenia as determined by an interview with the Structured Clinical Interview for DSM-III-R (9) and a best-estimate diagnostic meeting. Information from the structured diagnostic interview was supplemented by data from past psychiatric records and from available informants. Patients with concurrent drug abuse, alcoholism, organic brain disorder, mental retardation, or a medical condition that contraindicates use of clozapine or risperidone were excluded from the study. The age range of the subjects was 18–55 years.The patients met the following criteria for partial response to neuroleptics: 1) a history of residual positive and/or negative symptoms after at least a 6-week trial of a therapeutic dose of a neuroleptic agent, 2) at least a minimum level of positive and/or negative symptoms at the time of evaluation for the study, and 3) at least a minimum level of positive and/or negative symptoms after a prospective trial of at least 2 weeks of fluphenazine, 20 mg/day (with dose adjustments between 10 mg/day and 30 mg/day allowed in order to optimize outcome). The minimum positive symptom level was a total score of at least 8 for the four Brief Psychiatric Rating Scale (BPRS) (10) positive symptom items (conceptual disorganization, hallucinations, unusual thought content, and suspiciousness). The minimum negative symptom level was a total score on the Scale for the Assessment of Negative Symptoms (SANS) (11) of at least 20.All patients were stabilized on a regimen of fluphenazine for a minimum of 2 weeks, with the exception of one patient who was maintained on thioridazine, 600 mg/day, because of a history of intolerance to fluphenazine. Then, a subgroup of the total study group underwent a drug-free period for participation in other research protocols. All patients were then randomly assigned to treatment with clozapine or risperidone in a 6-week, parallel-group, double-blind comparison trial. Over the first 2 weeks, study medications were gradually increased to 400 mg/day of clozapine and 6 mg/day of risperidone. Clinicians’-choice adjustments were permitted over the next 2 weeks within fixed limits (200 mg/day and 600 mg/day for clozapine and 2 mg/day and 9 mg/day for risperidone). Over the last 2-week period, study medications were held constant. Benztropine mesylate was allowed for extrapyramidal symptoms as needed, which was determined by blinded psychiatrists. Blood for monitoring WBC for agranulocytosis was drawn weekly from patients receiving both drugs to help maintain the blind.Positive symptoms were assessed by the sum of scores on the four BPRS psychosis items indicated above. In addition, BPRS withdrawal/retardation and anxiety/depression factor scores and the total score on the 18-item BPRS (range=18–126) were used. The SANS total score (range=0–125) was used to assess negative symptoms.The Simpson-Angus Rating Scale (12) (range of scores=0–51) was used to assess parkinsonian symptoms. The item that rates salivation was omitted because increased salivation is a common side effect of clozapine that is not part of a parkinsonian clinical picture. The Hamilton Depression Rating Scale (13) was used to assess depression. The symptom and parkinsonian ratings were conducted by a research psychiatrist blind to treatment assignment (two patients’ Hamilton depression ratings were unavailable for analysis). Monthly interrater reliability meetings were conducted throughout the study to minimize rater drift, and interrater reliabilities (intraclass coefficients) for the symptom scales were 0.75 or greater.Venous blood samples were drawn between 7:00 a.m. and 8:00 a.m. from 13 of the 14 patients assigned to clozapine and 14 of the 15 patients assigned to risperidone during the last fluphenazine treatment week and week 6 of double-blind treatment. Samples were collected in EDTA-containing tubes, immediately placed on ice, and centrifuged for plasma separation; the resultant plasma was frozen until assay. Prolactin levels were assayed with microparticle enzyme immunoassay (intra-assay and interassay variability: 2.8% and 1.1%, respectively), growth hormone was assayed with radioimmunoassay (intra-assay and interassay variability: 9.2% and 6.6%, respectively), and cortisol was assayed with fluorescence polarization immunoassay (intra-assay and interassay variability: 3.0% and 5.2%, respectively).In the statistical analysis, the efficacy of clozapine and the efficacy of risperidone were compared by using the data from the end of the double-blind study (week 6), with baseline ratings (i.e., those from the last week of fluphenazine treatment) as the covariates. The last week of fluphenazine treatment was used as the baseline because it provides the greatest generalizability of the findings to clinical practice (i.e., switching to atypical antipsychotics from chronic neuroleptic treatment) and maximizes uniformity across all subjects. There were no significant differences between clozapine and risperidone baseline data, and assumptions of parallel slopes were assessed before analyses of covariance. A secondary, within-treatment-group analysis was conducted by comparing fluphenazine baseline data with week 6 data for each study drug. Effect size was calculated for efficacy variables by dividing the treatment difference (clozapine change from baseline minus risperidone change from baseline) by the square root of the mean squared error.RESULTSTwenty-nine patients entered the neuroleptic baseline phase and completed the 6-week double-blind comparative study; 14 (eight male and six female) were randomly assigned to clozapine and 15 (11 male and four female) to risperidone. There were no significant differences in the two groups’ demographic and clinical admission characteristics (table 1). Nineteen of the 29 patients underwent a drug-free period before random assignment (nine patients subsequently assigned to clozapine had a mean of 19.4 drug-free days, SD=7.9, and 10 patients subsequently assigned to risperidone had a mean of 17.6 drug-free days, SD=8.2; t=0.50, df=17, p=0.60). Two prospective subjects relapsed before random treatment assignment, and three were not successfully changed over to fluphenazine for baseline assessments; these five patients were not among the 29 subjects in the study analyses.Clozapine was superior to risperidone for BPRS positive symptoms and Simpson-Angus scores, but study drug comparisons revealed no significant differences on two measures of negative symptoms (SANS score and BPRS withdrawal/retardation score), BPRS total score, BPRS anxiety/depression score, and Hamilton depression score (table 2). A secondary within-group analysis comparing baseline and week 6 scores of the clozapine-treated patients revealed significant decreases in BPRS positive symptoms (F=13.9, df=1, 13, p=0.002), BPRS anxiety/depression (F=11.9, df=1, 13, p=0.004), BPRS total scores (F=18.9, df=1, 13, p=0.007), and Hamilton depression scores (F=13.0, df=1, 13, p=0.003). There were no significant differences between baseline and week 6 scores of the risperidone-treated patients. Using 20% change in BPRS total score to identify categorical responders, we found that five (35.7%) of the 14 patients assigned to clozapine and three (20.0%) of the 15 patients assigned to risperidone met the response criteria (χ2=0.9, df=28, p=0.34).The mean daily dose during week 6 was 403.6 mg/day (SD=79.6) for clozapine and 5.9 mg/day (SD=1.6) for risperidone. Three of the 15 risperidone patients had doses above 6 mg/day. Two patients assigned to clozapine and 10 patients assigned to risperidone received benztropine for extrapyramidal side effects during the trial (χ2=8.2, df=28, p=0.004).The assumptions of parallel slopes for the analysis of covariance for the prolactin data (F=8.9, df=1, 23, p=0.006) and the growth hormone data (F=4.7, df=1, 23, p=0.04) were not met, and therefore we did an analysis that compared the mean change scores (week 6 minus baseline) for the neuroendocrine data. There were significantly different effects of clozapine and risperidone on prolactin levels, with decrements from baseline to week 6 during clozapine treatment (table 3). A secondary analysis including only male patients’ prolactin data was conducted, and the results were still significant (t=3.6, df=17, p=0.001). There were no significant differences between the drugs for cortisol and growth hormone (table 3).DISCUSSIONThe results of this study indicate that clozapine is superior to risperidone for positive symptoms and extrapyramidal side effects, but differences were not found on two measures of negative symptoms, total symptom scores, and depression scores. Clozapine but not risperidone demonstrated significant reductions from fluphenazine baseline values in positive symptoms, total symptoms, and depression. In addition, clozapine produced fewer effects on plasma prolactin than either risperidone or fluphenazine, but significant differences were not found for growth hormone or cortisol.The data demonstrating clozapine’s superior efficacy for psychosis are consistent with data from previous clinical trials. In several studies (15–19), clozapine has shown superiority to traditional neuroleptics for positive symptoms. Although risperidone demonstrates superiority to placebo for positive symptoms, it has not consistently shown superiority to traditional neuroleptics for positive symptoms (20–23), suggesting that clozapine may be more effective for the psychosis of schizophrenia, particularly in more chronically ill, less neuroleptic-responsive populations. We found no significant differences between the two agents for negative symptoms as assessed with both the BPRS withdrawal/retardation subscale and the SANS total score. Moreover, neither drug demonstrated significant reductions in negative symptoms from the fluphenazine baseline. In several but not all previous studies (15–22, 24), both agents demonstrated superiority to neuroleptics for negative symptoms. However, in the one previous study of a priori defined partially responsive schizophrenic patients (17), clozapine’s effects on negative symptoms were modest, suggesting that this subgroup may have relatively treatment-resistant negative symptoms beyond what is treatable with traditional neuroleptics (17, 25). The baseline negative symptoms in the current study were determined after a fluphenazine trial. There were no significant differences in depression between the clozapine and risperidone groups in the comparative analyses; however, the clozapine-treated patients demonstrated reductions from fluphenazine baseline in depression scores, which is consistent with previous reports noting clozapine’s greater efficacy for mood symptoms in comparison with neuroleptic drugs (15, 26).In two comparative clinical trials (27, 28), clozapine and risperidone were found to have similar effects on symptoms. Klieser et al. (27) included patients with acute exacerbation of symptoms who did not meet a priori criteria for lack of response to treatment or partial response. Thus, differences in patients’ clinical status at the time of study entrance (acutely ill versus stabilized on fluphenazine) and patient subtype (less chronically ill versus partially unresponsive to neuroleptics) may account for the differing results in the Klieser et al. study and the present study. Other differences that may have contributed to the discrepant results were a shorter treatment period (28 days) and fixed dosing arms (risperidone, 4 mg/day and 8 mg/day, and clozapine, 400 mg/day) in the study by Klieser and colleagues as opposed to flexible dosing designed to optimize clinical outcomes in the current study. In the study by Bondolfi et al. (28), the mean daily dose of clozapine (291.2 mg) was lower than the dose in the present study and in other North American trials in treatment-resistant or partially responsive patients, which may account for differences between the results of their study and ours. In addition, the number of months of previous hospitalization in the study by Bondolfi and colleagues was approximately twice that in the current study, suggesting that their subjects may have been more treatment-resistant and chronically ill than our subjects. The Bondolfi et al. study’s treatment duration (8 weeks), risperidone dose (6.4 mg/day), and sociodemographic composition of the sample were roughly similar to those in the current study and are not a likely explanation for the discrepant findings.The lower incidence of extrapyramidal side effects associated with clozapine is consistent with previous data from primate models and clinical studies. Casey (5) demonstrated that risperidone has a steep dose-response curve for inducing dystonia in nonhuman primates—a predictive model of liability to extrapyramidal side effects in clinical populations. In contrast, even with exceedingly high doses, clozapine does not produce dystonia in primate models( 5). In clinical populations, risperidone is associated with dose-dependent induction of parkinsonian symptoms, with extrapyramidal side effects occurring in the upper dosage range (>6 mg/day) (20, 22). In contrast, clozapine is rarely associated with induction of extrapyramidal side effects in clinical populations, even at high dosages (15–18). Our finding of a lower use of benztropine in clozapine-assigned patients than in those receiving risperidone supports the more favorable extrapyramidal side effects profile of clozapine.Clozapine’s relative lack of effects on plasma prolactin levels compared with risperidone and fluphenazine is consistent with previous reports (6, 7, 29) and is probably attributable to those agents’ differential effects on dopamine neurotransmission. Dopaminergic tuberoinfundibular pathways have an inhibitory effect on pituitary prolactin release that is disrupted with administration of potent dopaminergic antagonists. Both in vitro binding studies and in vivo human imaging studies demonstrate higher dopamine D2 binding for neuroleptics and risperidone in comparison with clozapine (2–4, 16, 30, 31, and unpublished manuscript by Su et al., 1996). Moreover, in normal cultured rat pituitary cells, clozapine does not interfere with dopamine-mediated prolactin inhibition (6). Since antipsychotic-drug-related extrapyramidal side effects and prolactin elevations tend to be associated, it is tempting to speculate that lower doses of risperidone that do not induce extrapyramidal side effects would be less likely to induce prolactin increases.A few caveats should be considered in interpreting the findings of this study. The optimal dose of risperidone for comparative clinical trials is unclear. According to the literature (20, 22), lower doses (i.e., <6 mg/day) are associated with a more favorable extrapyramidal side effects profile and perhaps better effects on negative symptoms, and prescribing trends demonstrate greater utilization of lower risperidone doses (e.g., 4 mg/day). Even though only 20% of the risperidone-assigned patients in the current study had doses in excess of 6 mg/day, it will be important to examine the efficacy of lower risperidone doses in this population. The trial duration (6 weeks) and study group size (N=29) may have limited the detection of differences in specific domains, such as negative symptoms and rates of response. The patients participated in a prospective trial of fluphenazine to establish partial response to neuroleptics and to allow baseline ratings of psychopathology before random assignment to a drug. Thus, the patients’ baseline values reflected relative clinical stability, which may contribute to less variance and potential for symptom change than a baseline at the time of acute exacerbation. Given the a priori admission criteria, it is unclear whether our findings are generalizable to other schizophrenia subgroups.In conclusion, the data presented here indicate that these two second-generation agents have both important differences and similarities in their efficacy in schizophrenic patients who are partially responsive to typical neuroleptics. Clozapine had advantages for positive symptoms, extrapyramidal side effects, and prolactin levels, whereas differences in negative symptoms, total symptoms, depression, growth hormone, and cortisol were not found. Future research in partially responsive patients that addresses methodological issues such as optimal dose and treatment duration are needed.Received Oct. 9, 1997; revisions received March 11, July 9, and Aug. 24, 1998; accepted Sept. 1, 1998. From the Experimental Therapeutics Branch, Division of Intramural Research Programs, NIMH, Bethesda, Md. Address reprint requests to Dr. Breier, Eli Lilly & Co., Lilly Corporate Center, Drop Code 0538, Indianapolis, IN 46285; [email protected] (e-mail).TABLE 1Enlarge tableTABLE 2Enlarge tableTABLE 3Enlarge tableReferences1. Meltzer HY, Matsubara S, Lee J-C: Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2, and serotonin2 pKi values. 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Arch Gen Psychiatry 1992; 49:538–544Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByWhy Olanzapine Beats Risperidone, Risperidone Beats Quetiapine, and Quetiapine Beats Olanzapine: An Exploratory Analysis of Head-to-Head Comparison Studies of Second-Generation AntipsychoticsStephan Heres, M.D., John Davis, M.D., Katja Maino, M.D., Elisabeth Jetzinger, M.D., Werner Kissling, M.D., and Stefan Leucht, M.D.1 February 2006 \| American Journal of Psychiatry, Vol. 163, No. 2Clozapine, Olanzapine, Risperidone, and Haloperidol in the Treatment of Patients With Chronic Schizophrenia and Schizoaffective DisorderJan Volavka, M.D., Ph.D., Pal Czobor, Ph.D., Brian Sheitman, M.D., Jean-Pierre Lindenmayer, M.D., Leslie Citrome, M.D., M.P.H., Joseph P. McEvoy, M.D., Thomas B. Cooper, M.A., Miranda Chakos, M.D., and Jeffrey A. Lieberman, M.D.1 February 2002 \| American Journal of Psychiatry, Vol. 159, No. 2A Double-Blind Comparative Study of Clozapine and Risperidone in the Management of Severe Chronic SchizophreniaJean-Michel Azorin, M.D., René Spiegel, Ph.D., Gary Remington, M.D., Ph.D., Jean-Marie Vanelle, M.D., Jean-Jacques Péré, M.D., Monique Giguere, Ph.D., and Isabelle Bourdeix, Ph.D.1 August 2001 \| American Journal of Psychiatry, Vol. 158, No. 8Effectiveness of Second-Generation Antipsychotics in Patients With Treatment-Resistant Schizophrenia: A Review and Meta-Analysis of Randomized TrialsMiranda Chakos, M.D., Jeffrey Lieberman, M.D., Elaine Hoffman, Ph.D., Daniel Bradford, M.D., and Brian Sheitman, M.D.1 April 2001 \| American Journal of Psychiatry, Vol. 158, No. 4Risperidone Treatment for Psychosis in End-Stage Friedreich’s AtaxiaMATT J. SALBENBLATT, M.D. , RANDALL D. BUZAN, M.D., and STEVEN L. DUBOVSKY, M.D., 1 February 2000 \| American Journal of Psychiatry, Vol. 157, No. 2Bright Light Therapy’s Effect on Postpartum DepressionMARIA CORRAL, M.D., F.R.C.P.C., ANNIE KUAN, B.A., and DEMETRA KOSTARAS , B.SC., M.A., 1 February 2000 \| American Journal of Psychiatry, Vol. 157, No. 2Comparison of Clozapine and RisperidoneROBERT M. HAMER, PH.D., and PIPPA M. SIMPSON, PH.D., 1 February 2000 \| American Journal of Psychiatry, Vol. 157, No. 2 Volume 156Issue 2 February 1999Pages 294-298 Metrics PDF download History Published online 1 February 1999 Published in print 1 February 1999	Breier AF	1999	Am J Psychiatry	https://doi.org/10.1176/ajp.156.2.294	9989566	Breier AF; Malhotra AK; Su TP; Pinals DA; Elman I; Adler CM; Lafargue RT; Clifton A; Pickar D	article	D016430: Clinical Trial; D003160: Comparative Study; D016428: Journal Article; D016449: Randomized Controlled Trial	D000328: Adult; D014150: Antipsychotic Agents; D001480: Basal Ganglia Diseases; D002908: Chronic Disease; D003024: Clozapine; D004311: Double-Blind Method; D004334: Drug Administration Schedule; D005260: Female; D019382: Human Growth Hormone; D006801: Humans; D006854: Hydrocortisone; D008297: Male; D010302: Parkinson Disease, Secondary; D011388: Prolactin; D011569: Psychiatric Status Rating Scales; D018967: Risperidone; D012559: Schizophrenia; D012565: Schizophrenic Psychology; D016896: Treatment Outcome	None	None	https://openalex.org/W1821837697

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